Metabolic interactions between tumor cells and the immunce system in GBM A potential Achilles heel of GBM for novel therapeutics

GBM 中肿瘤细胞与免疫系统之间的代谢相互作用是 GBM 新疗法的潜在致命弱点

• 批准号: 10673172
• 负责人: Loic Pierre Deleyrolle
• 金额: $ 41.7万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673172
• 关键词: Affect; Apolipoprotein E; Biology; Brain Neoplasms; C57BL/6 Mouse; Cell Communication; Cell Compartmentation; Cell Cycle; Cell Lineage; Cell Shape; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Clinical; Communication; Complex; Coupled; Dependence; Disease; Disease Outcome; Disease Progression; Environment; Exhibits; FABP3 gene; Fatty Acids; Flow Cytometry; Genetic; Glioblastoma; Glioma; Glucose; Goals; Growth; Heterogeneity; Image; Immune; Immune checkpoint inhibitor; Immune system; Immunological Models; In Vitro; Induction of Apoptosis; Intervention; Investigation; Knockout Mice; LCN2 gene; Label; Laboratories; Link; Lipids; Logic; Macrophage; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid-derived suppressor cells; Nature; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Phenotype; Play; Population; Proliferating; Recurrence; Recurrent disease; Regulatory T-Lymphocyte; Reporting; Research Design; Resistance; Role; Shapes; Signal Transduction; Sorting; Specimen; System; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Transgenic Mice; Translating; Tumor Immunity; Tumor Promotion; Work; adipokines; aerobic glycolysis; anti-PD1 therapy; atorvastatin; cancer cell; cancer therapy; chemotherapy; clinically relevant; comparative; cytokine; digital; experimental study; genomic profiles; immune cell infiltrate; improved; in vivo; insight; intercellular communication; lipid biosynthesis; lipid metabolism; lipid transport; mortality; neoplastic cell; novel therapeutics; pharmacologic; programs; recruit; single-cell RNA sequencing; standard of care; temozolomide; therapeutic evaluation; therapy resistant; transcriptomics; tumor; tumor heterogeneity; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic; uptake

ABSTRACT Background: We recently revealed that glioblastoma (GBM) contain cell populations with distinct metabolic requirements, with fast-cycling cells (FCCs) harnessing aerobic glycolysis, and treatment-resistant slow-cycling cells (SCCs) preferentially engaging lipid metabolism. How the different tumor cells interact with immune cells and how this metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood. Objectives/Hypothesis: The objectives of this study are to understand the mechanisms of communication in the tumor microenvironment, specifically to characterize the metabolic interactions between SCCs (a therapeutically resistant population that drive disease progression and recurrence) and the immune compartment. Here, we will investigate a model of intercellular communication within GBM where SCCs shape an immunosuppressive tumor milieu, which in turn assume metabolic support to SCCs by providing them with lipids, which are essential for SCC metabolism and function. Importantly, we will test multiple genetic and clinically amenable pharmacological approaches disrupting this metabolic interplay to antagonize GBM. Specific aims: Our specific aims will be 1) Dissect the relationship of SCCs with the tumor microenvironment, 2) Delineate how recruited immune suppressive cell mediate SCC-driven tumor progression, and 3) Establish that immune infiltrates provide metabolic support to SCCs by providing lipids. Study design: The link between tumor heterogeneity and tumor immune landscape in GBM will be deciphered with specific investigations of the metabolic interplay taking place between these cellular compartments. In aim 1, we will delineate the cell lineage (SCC vs FCC) relationship with immune infiltrates by investigating their genomic profile and spatial organization, using single cell RNA sequencing technology and GeoMx Digital Spatial Profiling, respectively. We will also evaluate the role of the specific adipokine, Lipocalin-2, in shaping the immune microenvironment. In aim 2 we will employ multiple approaches disrupting the macrophage, myeloid- derived suppressor cell, and regulatory T cell compartments, and compare the effect on survival, growth and chemotherapy sensitivity of SCCs and FCCs. In aim 3 the use of fluorescently labeled lipids combined with flow cytometry and time lapse imaging will enable the comparison of lipid transfer between immune cells, FCCs and SCCs. Finally, in vivo experiments will test the hypothesis that targeting lipid trafficking (inhibition of FABP3 or ApoE) or lipogenesis (statin treatment) provide therapeutic benefits by affecting SCCs and rendering the overall tumor more responsive to chemotherapy. Based on the recently reported synergistic effect of statins with immune checkpoint inhibitors, we will also evaluate the combination of statins with anti PD-1 therapy. Impact: Successfully completed, this project will validate therapeutically amenable approaches targeting metabolic communication to improve brain tumor associated morbidity and mortality.

摘要 背景：我们最近发现，胶质母细胞瘤（GBM）含有不同代谢的细胞群， 快速循环细胞（FCC）利用有氧糖酵解， 细胞（SCC）优先参与脂质代谢。不同的肿瘤细胞如何与免疫细胞相互作用 以及这种代谢异质性如何塑造GBM中的免疫景观还有待了解。 目的/假设：本研究的目的是了解沟通的机制， 肿瘤微环境，特别是表征SCC之间的代谢相互作用（a 驱动疾病进展和复发的治疗抗性群体）和免疫区室。 在这里，我们将研究GBM内细胞间通讯的模型，其中SCC形成一个 免疫抑制性肿瘤环境，其反过来通过向SCC提供脂质而承担对SCC代谢支持， 其对于SCC代谢和功能是必需的。重要的是，我们将测试多种遗传和临床 干扰这种代谢相互作用以拮抗GBM的可行的药理学方法。 具体目标：我们的具体目标将是1）解剖SCC与肿瘤微环境的关系， 2)描述募集的免疫抑制细胞如何介导SCC驱动的肿瘤进展，以及3）建立 免疫浸润通过提供脂质为SCC提供代谢支持。 研究设计：GBM中肿瘤异质性和肿瘤免疫景观之间的联系将被破译 并对这些细胞间的代谢相互作用进行了具体研究。 在目的1中，我们将通过研究细胞谱系（SCC vs FCC）与免疫浸润的关系， 他们的基因组概况和空间组织，使用单细胞RNA测序技术和GeoMx数字 空间轮廓，分别。我们还将评估特定的脂肪因子Lipocalin-2在形成脂肪细胞中的作用。 免疫微环境在目标2中，我们将采用多种方法破坏巨噬细胞，骨髓- 衍生的抑制细胞和调节性T细胞区室，并比较对存活、生长和 SCC和FCC的化疗敏感性。在aim 3中，使用荧光标记的脂质与流动相结合， 流式细胞术和延时成像将能够比较免疫细胞、FCC和 SCC。最后，体内实验将测试靶向脂质运输（FABP 3或FABP 4的抑制）的假设。 ApoE）或脂肪生成（他汀类药物治疗）通过影响SCC并使整体SCC 肿瘤对化疗更敏感基于最近报道的他汀类药物与免疫系统的协同作用， 检查点抑制剂，我们还将评估他汀类药物与抗PD-1治疗的组合。 影响：成功完成后，该项目将验证适合治疗的方法， 代谢通讯，以改善脑肿瘤相关的发病率和死亡率。